The prolonged delivery of active agents orally has been a long-desired objective in drug therapy. It is often desirable to administer a single dose of medication which releases the active ingredient over an extended period of time rather than to administer a number of single doses at regular intervals.
Osmotic dispensing devices for delivery of therapeutically active agents are well known in the art and have been used for the oral administration of drugs. Such devices use an expansion means to deliver an agent to an environment of use over a period of hours, days or months. The expansion means absorbs liquid, expands, and acts to drive out beneficial agent formulation from the interior of the device in a controlled, usually constant manner. The osmotic expansion means is used to controllably, usually relatively slowly, and over a period of time, deliver the agent.
However, long-term oral delivery has been difficult to achieve due to the 8-16 hour gastrointestinal transit time of an ingested substance. In order to achieve uninterrupted action for longer than 24 hours by a therapeutic substance, its passage needs to be slowed in the gastrointestinal tract or the delivery device supplying the drug has to be fixed or immobilized within the tract.
Additionally, certain classes of drugs or active agents are not adequately absorbed during their relatively brief passage through the gastrointestinal tract. This can be due to either their physicochemical properties or their requirement of a particular site of absorption, as is discussed by Tossounian et al. in Drug Dev. Indus. Pharm. (1985) 11:1019-1050. For example, certain drugs are better solubilized in the acidic medium of the stomach rather than in the neutral or alkaline environment of the intestine. Also, many active agents and vitamins are principally absorbed from the upper portion of the small intestine. Other compounds are intended to act in the stomach contents and will lose their beneficial effects if they pass into the intestine.
One method widely used to obtain a necessary or beneficial drug level in the upper gastrointestinal tract over a number of hours comprises administering a number of pills or tablets at regular time intervals to achieve a dose frequency response relationship. However, this method has certain inherent limitations that tend to defeat its purpose. For example, the pills often are rapidly cleared from the gastrointestinal tract before they are fully utilized. Also, the administration of a number of pills at set times over a prolonged period requires attention by the user and frequently a particular administration is inadvertently overlooked, which diminishes the results of this method. Thus, a graphic illustration of the drug's concentration in the blood during a dosage schedule for this method has the appearance of a series of peaks and valleys, rather than a fairly continuous level concentration; and often these valleys may fall below the drug concentration needed to achieve the desired beneficial effects or the peaks rise dangerously above the concentration that is necessary.
Another approach is to provide a sustained release of the agent. Previous sustained release preparations have included active agents that are either coated with varying thicknesses of a relatively insoluble polymer or are embedded into the matrix of water-insoluble ingredients to provide a continuous amount of agent for absorption. However, the dosage forms pass through the gastrointestinal tract without being slowed or immobilized. They are not retained in the stomach for any longer time than a conventional capsule, tablet or pill and hence do not provide administration of drug to the stomach or upper portion of the small intestine for any prolonged period.
Attempts have been made either to incorporate drugs into floating devices which would empty less readily from the stomach (New Eng. J Med. (1981) 304:1365-1366; Tossounian, supra) or to introduce balloon-based devices which could be inflated by propellants or be fluid-expanded in the stomach after the whole device has been swallowed (U.S. Pat. Nos. 3,786,813; 3,788,322; 3,797,429; 3,901,232; 4,207,890; and 4,925,446). One problem with such devices is that often they cannot exit the stomach or exit only with difficulty. This can cause discomfort to the user, and the accumulation of many devices in the stomach can pose serious health problems. Additionally, the rate and/or duration of release of drug from the devices or the duration of the devices within the stomach often cannot be controlled with accuracy. Also, several of these devices are of rather elaborate design, making them difficult to manufacture and expensive.
There remains a continuing need for a practical gastrointestinal drug delivery device that is relatively simple, safe to use, and able to release significant quantities of active agent in a controlled manner over a prolonged period of time into the stomach environment.